The monoacylglycerol lipase inhibitors MAFP and JZL184 potentiate 2-arachidonoylglycerol and 1-arachidonoylglycerol sensory nerve-mediated vasodilation.

<p>(A) Concentration-response curves for (i) 2-arachidonoylglycerol (2-AG), (ii) 1-arachidonoylglycerol (1-AG), and (iii) anandamide (AEA) in the presence of MAFP (n = 6–11), JZL184 (n = 6–8) or vehicle (n = 13–18). The area under the curve was larger in the presence than in the absence of MAFP (<i>P</i><0.05, 2-AG; <i>P</i><0.001, 1-AG) or JZL184 (<i>P</i><0.05, 2-AG; <i>P</i><0.001, 1-AG). (iv) Concentration-response curves for noladin ether (NE), the stable analog of 2-AG (n = 6–8). The vasodilation evoked by 2-AG, 1-AG, AEA and NE but not arachidonic acid were abolished by capsaicin pretreament (A–D). Traces show vasodilator responses to (B) 2-AG, (C) 1-AG and (D) arachidonic acid after pretreatment with vehicle (left) or capsaicin (right) to cause desensitization and/or neurotransmitter depletion of sensory nerve endings in rat mesenteric arteries. Subsequent application of acetylcholine (ACh) was used to confirm that arteries were able to respond with vasorelaxation (mediated by endothelium-derived hyperpolarising factor; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081618#pone.0081618-Zygmunt4" target="_blank">[83]</a>). The capsaicin pretreatment consisted of a 30 min exposure to 10 µM capsaicin followed by washout of capsaicin. The arterial segments were submaximally contracted with phenylephrine (PhE) before addition of the test drugs. The dashed line shows the basal tension level before addition of PhE. MAFP (30 nM) was present in experiments with 2-AG (B) and 1-AG (C). Control experiments were performed in the presence of vehicle (0.1% ethanol). Data are expressed as mean ± s.e.m.